TALOS-AMI Supports Clopidogrel De-escalation After Earlier Ticagrelor Post-PCI

A de-escalation antiplatelet strategy of switching from the more-potent ticagrelor (Brilinta; AstraZeneca) to clopidogrel at 1 month after PCI for acute MI is superior to continuing on ticagrelor and aspirin in terms of net clinical benefit, according to the TALOS-AMI trial.

“This study was conducted only in South Korea. However, although the prevalence of the CYP2C19 loss-of-function allele is significantly higher in Koreans than in other ethnic groups, this study showed the clinical safety of switching in this population, suggesting the potential of applying this de-escalation strategy to other ethnic groups,” said Kiyuk Chang, MD, PhD (The Catholic University of Korea, Seoul, Republic of Korea), who presented the findings in a late-breaking clinical trial session yesterday at the American College of Cardiology 2021 Scientific Session.

Clinicians have debated the pros and cons of de-escalation since the TOPIC trial first pointed to the cost savings and reduced bleeding seen when switching to a less potent P2Y12 inhibitor. Others have argued that the potential increased risk of ischemic events in these patients needs to be carefully weighed against the advantages. In SWAP-4, trialists proposed a loading dose of clopidogrel might help with the transition, but the ultimate optimal strategy remains up in the air.

“I think this is going to have major implications for how we practice in taking care of our patients after acute MI,” Claire Duvernoy, MD (University of Michigan Health System, Ann Arbor), commented during a press conference. “The fact is that many of us here in the States use this strategy both for cost reasons, for tolerability reasons, and for safety reasons. And what your study has shown us is that what we are already doing in the absence of great evidence appears to be both a safe and effective strategy. So I'm very pleased to see these results and I expect that this will further lend credence to what we are already doing certainly in the United States.”

Additionally, Duvernoy said she was glad to see that the researchers did not perform platelet function testing, “because to be honest that's not done routinely in most places that I know of. And I think that gives confidence to us that it's not something that we must be doing and must be paying attention to.”

Less Bleeding, No Increase in Ischemic Events

For TALOS-AMI, Chang and colleagues randomized 2,697 Korean acute MI patients who had all received 1 month of dual antiplatelet therapy (DAPT) involving ticagrelor and aspirin with no events to either de-escalation with aspirin and clopidogrel (n = 1,349) or continued ticagrelor and aspirin (n = 1,348). Slightly more than half of all patients presented with STEMI, and the mean age was about 60 years. Notably, adherence was very high with more than 98% and 97% of de-escalated and control patients, respectively, remaining on their randomized therapies at 10 months.

After 2 weeks from randomization, none of the de-escalated patients had died or reported stent thrombosis, though there was a single case of non-target-lesion MI not related to stent thrombosis at day 5. There were no ischemic events in the active control group.

At 1 year, the risk of cardiovascular death, MI, stroke, or BARC 2, 3, or 5 bleeding (primary composite endpoint) was almost halved in patients in the de-escalation group compared with controls (4.6% vs 8.2%; HR 0.55; 95% CI 0.40-0.76). This difference was driven by less bleeding (3.0% vs 5.6%; HR 0.52; 95% CI 0.35-0.77); there was no significant difference when looking at ischemic events alone (2.1% vs 3.1%; HR 0.69; 95% CI 0.42-1.14).

Results were maintained in a variety of subgroup analyses including clinical presentation, gender, age, diabetic status, LVEF, and estimated glomerular filtration rate.

Chang noted that the event rates observed in TALOS-AMI were slightly lower than had been estimated for both the de-escalation and active control groups.

Generalizability to Other Populations?

In discussion following Chang’s presentation, Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), said she was “baffled” as to why the researchers combined the major ischemic endpoints with bleeding for their primary analysis, asking: “Are you confident that you have achieved noninferiority in the ischemic endpoints?”

In response, Chang pointed out that other de-escalation antiplatelet trials have shown rates of ischemic events similar to TALOS-AMI. “Our TALOS-AMI trial has the same ischemic event rate,” he observed, “so I'm sure [that] our TALOS trial shows noninferiority compared to aspirin plus ticagrelor.”

“I think that would be debatable,” Mehran persisted. “You would need a much, much larger [study] given the event rates that you've shown us. I guess in the context of other trials, maybe this could be an important observation to be evaluated going forward, because that is the most important question.”

Mehran also queried the low ischemic event rates, especially in the clopidogrel arm, given the greater prevalence of the loss-of-function CYP2C19 allele and the higher risk of bleeding generally seen in the Asian population.

To TCTMD, Duvernoy said she believed this is one of the study’s strengths. “Especially with the fact that the Korean population that was studied in this trial did have a high prevalence of the loss-of-function allele, [this] would have suggested that clopidogrel would be less effective. And yet the study found it to be efficacious and safer. To me that says that in other populations we may be able to apply these results, as well,” she explained. “Now I'd like to see this strategy studied in multi-ethnic populations before I say, ‘Yes, of course, no question,’ but to me this is very encouraging and potentially applicable to many other populations.”

Given the study’s rigorous follow-up protocol, Chang strongly agreed. “I'm sure that these results can be applied to other ethnic groups,” he said.